Methionine sulfoxide reductases are unique in their ability to actually repair oxidative stress damage through the direct reduction of oxidized methionine residues and are likely to play key roles in lens aging and cataract formation. MsrA activity has been detected in the human lens, and the oxidized methionine content of human lens proteins increases with age reaching levels as high as 60% in age-related cataract relative to clear human lenses. This proposal will test the hypothesis that methionine sulfoxide reductases defend the lens against oxidative stress damage and that decreased Msr levels and/or activities are associated with increased oxidation of lens methionines, lens damage and cataract. To test this hypothesis: (1) The identities, levels, activities and sub-cellular localization patterns of methionine sulfoxide reductases of the human and mouse lens will be established;(2) The ability of methionine sulfoxide reductases to defend the lens against oxidative-stress will be determined;and (3) the relationship between methionine sulfoxide reductase activity and methionine oxidation will be established in lens aging and age-related cataract. These aims will be accomplished using an integrative approach that functionally tests the in vitro and in vivo ability of methionine sulfoxide reductases to defend the lens against oxidative stress damage and directly examines methionine sulfoxide reductase activities in actual human lenses and cataracts. The feasibility of this work is supported by the initial identification and spatial characterization of three separate methionine sulfoxide reductase genes in the human lens and the demonstration that at least one of these genes, called MsrA, can directly defend lens cells against oxidative stress damage.